Safety and pharmacokinetics of abacavir (1592U89) following oral administration of escalating single doses in human immunodeficiency virus type 1-infected adults

Abacavir (1592U89) is a nucleoside analog reverse transcriptase inhibitor t hat has been demonstrated to have selective activity against human immunode ficiency virus (HIV) in vitro and favorable safety profiles in mice and mon keys. A phase I study was conducted to evaluate the safety and pharmacokine tics of abacavir following oral administration of single escalating doses ( 100, 300, 600, 900, and 1,200 mg) to HIV-infected adults. In this double-bl ind, placebo-controlled study, subjects with baseline CD4(+) cell counts ra nging from <50 to 713 cells per mm(3) (median, 315 cells per mm(3)) were ra ndomly assigned to receive abacavir (n = 12) or placebo (n = 6). The bioava ilability of the caplet formulation relative to that of the oral solution w as also assessed with the 300-mg dose. Abacavir was well tolerated by all s ubjects; mild to moderate asthenia, abdominal pain, headache, diarrhea, and dyspepsia were the most frequently reported adverse events, and these were not dose related. No significant clinical or laboratory abnormalities were observed throughout the study. All doses resulted in mean abacavir concent rations in plasma that exceeded the mean 50% inhibitory concentration (IC50 ) for clinical HIV isolates in vitro (0.07 mu g/ml) for almost 3 h. Abacavi r was rapidly absorbed following oral administration, with the time to the peak concentration in plasma occurring at 1.0 to 1.7 h postdosing. Mean max imum concentrations in plasma (C-max) and the area under the plasma concent ration-time curve from time zero to infinity (AUC(0-infinity)) increased sl ightly more than proportionally from 100 to 600 mg (from 0.6 to 4.7 mu g/ml for C-max; from 1.0 to 15.7 mu g.h/ml for AUC(0-infinity)) but increased p roportionally from 600 to 1,200 mg (from 4.7 to 9.6 mu g/ml for C-max; from 15.7 to 32.8 mu g.h/ml for AUC(0-infinity)). The elimination of abacavir f rom plasma was rapid, with an apparent elimination half-life of 0.9 to 1.7 h, Abacavir was well absorbed, with a relative bioavailability of the caple t formulation of 96% versus that of an oral solution (drug substance in wat er). In conclusion, this study showed that abacavir is safe and is well tol erated by HIV-infected subjects and demonstrated predictable pharmacokineti c characteristics when it was administered as single oral doses ranging fro m 100 to 1,200 mg.